Failure of early non-invasive ventilation in preterm infants with respiratory distress syndrome in current care practice in Spanish level-III neonatal intensive care units – a prospective observational study

Introduction Despite advances in respiratory distress syndrome (RDS) management over the past decade, non-invasive ventilation (NIV) failure is frequent and associated with adverse outcomes. There are insufficient data on the failure of different NIV strategies currently used in clinical practice in preterm infants. Methods This was a prospective, multicenter, observational study of very preterm infants [gestational age (GA) <32 weeks] admitted to the neonatal intensive care unit for RDS that required NIV from the first 30 min after birth. The primary outcome was the incidence of NIV failure, defined as the need for mechanical ventilation for <72 h of life. Secondary outcomes were risk factors associated with NIV failure and complication rates. Results The study included 173 preterm infants with a median GA of 28 (IQR 27–30) weeks and a median birth weight of 1,100 (IQR 800–1,333) g. The incidence of NIV failure was 15.6%. In the multivariate analysis, lower GA (OR, 0.728; 95% CI, 0.576–0.920) independently increased the risk of NIV failure. Compared to NIV success, NIV failure was associated with higher rates of unfavorable outcomes, including pneumothorax, intraventricular hemorrhage, periventricular leukomalacia, pulmonary hemorrhage, and a combined outcome of moderate-to-severe bronchopulmonary dysplasia or death. Conclusion NIV failure occurred in 15.6% of the preterm neonates and was associated with adverse outcomes. The use of LISA and newer NIV modalities most likely accounts for the reduced failure rate. Gestational age remains the best predictor of NIV failure and is more reliable than the fraction of inspired oxygen during the first hour of life.

Failure of early non-invasive ventilation in preterm infants with respiratory distress syndrome in current care practice in Spanish level-III neonatal intensive care unitsa prospective observational study Introduction Neonatal respiratory distress syndrome (RDS) is a disorder that mainly affects premature infants at <34 weeks of gestation. It occurs due to surfactant deficiency in the context of immature lungs, which prevents proper tissue oxygenation. RDS is a common cause of morbidity and mortality in preterm infants, with more severe diseases in smaller and more premature neonates.
The objective of respiratory management of preterm infants with or at risk of RDS is to maximize survival while minimizing potential adverse effects, such as bronchopulmonary dysplasia (BPD). The 2019 European Consensus Guidelines on the management of RDS recommend the early use of continuous positive airway pressure (CPAP) of at least 6 cm H 2 O in all babies at risk of RDS who do not need intubation for delivery room stabilization (1). Early initiation of CPAP potentially reduces the need for mechanical ventilation and surfactant replacement (2, 3) while improving clinical outcomes (2,4,5).
Although RDS management has evolved dramatically over the last decade, almost half of the infants who are started on CPAP fail this therapy and are ultimately intubated (6,7). It should be noted that CPAP failure is associated with an increased risk of death and morbidities, including BPD and pneumothorax (8)(9)(10).
Studies have shown that birth weight and male gender are risk factors for CPAP failure (9,(11)(12)(13). Furthermore, observational data demonstrate that a fraction of inspired oxygen (FiO 2 ) exceeding 0.30 in the first hours after birth in preterm neonates on CPAP is a reasonably good test to predict subsequent CPAP failure (9,14). However, non-adherence to the recommended FiO 2 threshold is common in clinical practice (15,16), which can have negative consequences such as the prolonged need for mechanical ventilation and increased incidence of adverse outcomes.
To mitigate CPAP failure, and in parallel with technological advances in the field of neonatal ventilators, different modes of non-invasive ventilation (NIV) have been introduced, with nasal intermittent positive-pressure ventilation (NIPPV) being the most frequently used alternative. This intervention has been found to have variable success rates in different studies (6,17,18). Heated and humidified oxygen delivered by a high-flow nasal cannula (HFNC) has also been studied as the first respiratory support. Still, it was found to be inferior to CPAP in terms of failure rate, and infants randomized to HFNC often need rescue therapy with CPAP to avoid intubation (19).
Although several studies have analyzed the factors associated with CPAP failure in premature infants, there is a lack of sufficient and updated data on the failure of the NIV methods currently used in clinical practice, including HFNC and NIPPV. We designed this observational and prospective study (VENTIS) to evaluate the incidence, predictive factors, and clinical outcomes of NIV failure in preterm infants at risk for RDS admitted to Spanish level-III neonatal intensive care units (NICUs).

Study design and patients
VENTIS was a prospective, multicenter, observational study of preterm infants with RDS initially managed with non-invasive respiratory support. Written informed consent was obtained from the parents or guardians of each patient. The study protocol was reviewed and approved in July 2019 by the Clinical Research Ethics Committee of Vall d'Hebron Hospital, Barcelona, and subsequently by the rest of the Institutional Review Boards of the participating hospitals.
This study was conducted at ten level-III NICUs in Spain between November 2019 and March 2021. Measures were taken according to the distribution of patients across the centers to avoid site effects.
Participants were eligible for the study if they were very preterm newborns [gestational age (GA) <32 weeks] admitted to the NICU for RDS requiring NIV (CPAP, NIPPV, or HFNC) in the first 30 min after birth. The ventilation method and administration of surfactant and/or caffeine citrate were performed according to the local clinical practice. The exclusion criteria were intubation in the delivery room, severe respiratory failure requiring mechanical ventilation from birth, clinical chorioamnionitis, prolonged premature rupture of membranes over 2 weeks, or the presence of a major congenital anomaly.

Data collection and endpoints
The primary outcome was the incidence of NIV failure, defined as the need for mechanical ventilation within the first 72 h of life. As secondary outcomes, we examined ventilatory outcomes and neonatal morbidities to identify the risk factors associated with NIV failure. The pregnancy and delivery characteristics recorded included antenatal corticosteroid use, mode of delivery, gestational age, sex, birth weight, and Apgar score. Furthermore, we collected data on the type of ventilatory support used, duration and timing of ventilation, ventilator and respiratory parameters, surfactant and/or caffeine administration, FiO 2 before surfactant administration, and moment of initiation of Kangaroo Mother Care. Clinical outcomes were also recorded, including hospital stay, duration of supplemental oxygen, need for home oxygen, neonatal morbidities/complications, including BPD (need for respiratory support and/or additional oxygen at 36 postmenstrual weeks), air leak syndrome, grade III-IV intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), retinopathy of prematurity (ROP) >2, patent ductus arteriosus (PDA) with surgical treatment, necrotizing enterocolitis (NEC) Bell stage ≥2, pulmonary hemorrhage, and death.
Data were collected using a case record form developed for this study. The inclusion visit was performed at 24 h of life, and the infants were followed up at 72 h and at hospital transfer, discharge, or death. Information corresponding to the first hour after birth was retrospectively recorded.

Statistical analysis
Based on the study by Dargaville et al. we estimated that NIV failure would occur in 22% of infants at risk of RDS (9). A sample size of 159 subjects provided an estimate of incidence with a 95% confidence interval (95%CI) with ±7% precision, accounting for 15% invalid data.
Descriptive analysis was performed by calculating frequencies and percentages for categorical variables. The central tendency (mean and median) and dispersion [standard deviation and interquartile range (IQR)] were calculated for quantitative variables. The independent sample t-test was used to compare continuous variables, and the χ 2 test or Fisher's exact test was used to compare categorical variables. All analyses are presented for the entire cohort and gestational age.
Multiple logistic regression was used to identify potential predictors of NIV success or failure by calculating odds ratios (OR) with 95% confidence intervals (CI). The variables selected for the multivariate analysis were those corresponding to p-values less than 0.1 in the univariate analysis. Statistical significance was set at p < 0.05; analyses were performed using the available data without imputation of the missing data. Statistical analyses were performed using the SAS software (version 9.3, SAS Institute Inc., Cary, NC, United States).

Patient characteristics
A total of 173 infants were included in the study. Figure 1 shows the flowchart of the study. All infants had complete data and were analyzed.
The characteristics of gestational and newborn infants are shown in Table 1, overall and by GA group. We observed that most pregnancies were singleton (61.8%), and 80.9% of women had received a complete course of antenatal corticosteroids. Cesarean section occurred in 66.6% of the cases. The proportion of male newborns in the study was 50.3%. The median birth weight was 1,100 g (IQR:800-1333).

Management of respiratory distress
NIV was initiated at a median time of 1.0 min (IQR:0-3) after birth, with CPAP being the most common type of NIV used as the first ventilatory support option ( Table 2)  Patient distribution in the VENTIS study. GA, gestational age.    Type of initial NIV, n (%)

Non-invasive ventilation outcome and risk analysis
In general, NIV failure occurred in 27 of 173 infants (15.6%). These infants ultimately required MV within the first 72 h of life. The frequency of NIV failure increased significantly with decreasing gestational age at birth (Figure 2). A total of 124 infants remained on NIV at 72 h of life. The treatment failure rate was 14.6% for CPAP and 17.1% for NIPPV.
To identify variables associated with the outcome of NIV, the success and failure groups of NIV were compared ( Table 3). The multivariate regression model confirmed a significant association between GA and NIV failure; the odds of escalation of therapy to MV before 72 h of life increased by 37% at each week of gestation (OR,0.728; 95% CI, 0.576-0.920). Prenatal corticosteroid use (no vs. yes; OR, 7.211; 95% CI, 1.218-42.701) and surfactant administration (no vs. yes; OR,0.054; 95% CI, 0.012-0.252) were also independently associated with NIV failure.
There was no difference in the incidence of moderate-to-severe BPD between the groups; however, the need for MV at <72 h of life was associated with significantly higher rates of the combined outcome of moderate-to-severe BPD or death (37% vs. 14.5%; p = 0.0114). Nine infants died during the study: two from NEC, one from parenchymal cerebral infarction, one from severe hypoxemic respiratory failure, one from pneumothorax, one from sepsis, and three from septic or cardiogenic shock. The mortality rates did not show statistically significant variation.
In the overall study population, 10.5% of infants had respiratory complications, and 15.7% had common complications of Non-invasive ventilation failure rate according to gestational age.    Table 4).

Discussion
Our observational study included 173 very preterm infants (GA < 32 weeks) who underwent NIV within the first 30 min after birth. The global incidence of NIV failure was 15.6%, and these patients required invasive MV for 72 h. This study allowed us to obtain new data on the global success of NIV in current clinical practice, including the most widely used NIV methods today. In our cohort, 56% of patients underwent CPAP, and 44% had NIPPV in the first 24 h of life. NIPPV was used more often to treat more immature babies and as rescue therapy for those about to fail. Therefore, individual analysis of NIPPV failure could not be performed. European guidelines recommend initiating CPAP of at least 6 cm H 2 O, but the mean pressure with CPAP was significantly lower than with NIPPV on the first hour (5.4 vs. 7.1 cm H 2 O) and this difference persisted throughout. It appears that use of NIPPV enabled clinicians to apply adequate distending pressure.
Previous studies focused only on the CPAP technique and found a higher percentage of failure (failure rates: 20.  (20). According to our data, if we consider only patients who underwent CPAP in the first 24 h of life, the failure rate was 14.6%. However, we must remember that the aforementioned studies included infants with different GA ranges, the use of LISA or INSURE was not standardized, and the most severe cases of RDS were treated with NIPPV. Dargaville et al. studied a cohort of 25-32 weeks GA patients in a large retrospective study and found a CPAP failure rate of 22%. Given that nearly a decade has passed since the Dargaville study, the higher percentage of success obtained in our cohort can be interpreted as an advance in the use of NIV and surfactant administration techniques or, in general, an improvement in early respiratory management in these patients (20). The Dargaville definition of CPAP failure is the need for mechanical ventilation within 72 h after birth. We used the same definition, but most of our patients received surfactant by a non-invasive technique and were kept on NIV. Therefore, despite using the same definitions, the groups were not comparable.
Given that new NIV methods are being used in addition to CPAP, and its early use has been shown to reduce the use of MV while improving clinical outcomes, it is of utmost importance to know which factors are predictive of NIV failure. Early identification of those premature infants who most likely fail NIV can allow specific therapeutic interventions to be aimed at them. The final multivariate model identified GA as an independent predictor of NIV failure. The risk of unfavorable outcomes increased by 37% with each week of gestational age. Gestational age has been associated with CPAP failure. Gulczyńska et al. found that each gestational week reduced the odds of CPAP failure by 19% in infants with <30 GA (19). Dargaville et al. found a significant association in the most premature infants, 25-28 weeks of GA, in whom each additional week reduced the risk of failure by 39% (9). However, in both cases and unlike our study, GA did not prove to be an independent predictor in multivariate logistic regression.
Interestingly, FiO 2 between the second and sixth hours of life was predictive of failure in our univariate model but was not   (1,9). Due to the observational nature of the present study, the surfactant was administered following clinical practice, with a median FiO 2 slightly higher than that recommended in the European guidelines (1). Therefore, the statistically significant association between surfactant use and NIV failure should be interpreted with caution. This association probably exists because the VENTIS is an observational study and was not designed to evaluate the use of surfactants. All patients with mild RDS who did not receive surfactant were in the NIV success group, and all patients who failed NIV received surfactant at the time of intubation. Furthermore, the correct timing of surfactant use may have contributed to a higher percentage of success of noninvasive techniques. Therefore, proper adherence to the recommendations of the current European RDS guidelines can be confirmed. Early administration of surfactants, especially with the LISA technique using a thin catheter while continuing CPAP, reduces the need for subsequent MV (22-26). Infants for whom NIV failed were at a considerably higher risk of adverse outcomes and morbidity than those successfully managed with NIV (9,14,20). Non-invasive ventilation failure was associated with a higher percentage of BPD and the composite outcome of moderate-to-severe BPD plus death. However, the number of deaths did not differ significantly between the success and failure groups. Furthermore, noninvasive respiratory support failure was associated with higher rates of other unfavorable outcomes, including pneumothorax, IVH, PVL, and pulmonary hemorrhage. All these complications have previously been related to RDS and prematurity, especially in seriously ill infants who need MV because non-invasive support fails. As in the Dargaville study, the duration of hospital stay and oxygen therapy was significantly higher in infants who failed NIV. We also observed that the need for home oxygen at discharge and duration of NIV were significantly higher in the failure group than in the success group. Our data show that the predictive variables for NIV failure evolve towards GA rather than FiO 2 in the initial hours if the current threshold recommendations for surfactant administration are followed. There is a need to improve respiratory management in premature infants to avoid unfavorable outcomes.
Our study had some limitations. This was an observational study, and the results obtained showed the variability of real-life clinical practice. Although we recorded the PEEP and MAP (median and IQR) for CPAP and NIPPV at intervals (first hour of life, first 24 h of life, 24-72 h of life), we did not record the level of support immediately before failure.

Conclusion
The incidence of NIV failure in our cohort of very preterm infants managed according to current RDS respiratory management standards was 15.6%. The lower failure rate observed compared with previous studies is most likely due to LISA and the newer NIV modes currently used in our units. The use of NIPPV likely facilitated the use of higher distending pressure. Gestational age remains the best predictor of NIV failure as primary respiratory support in premature infants. FiO 2 during the first hours of life was not an independent risk factor for NIV failure in our cohort, confirming that FiO 2 > 0.3 is a good indicator for surfactant administration as recommended in the European guidelines for the management of RDS.

Data availability statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethics statement
The studies involving human participants were reviewed and approved by Clinical Research Ethics Committee of the Vall d'Hebron Hospital, Barcelona, Spain, and subsequently by the Institutional Review Boards of the participating hospitals. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.

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